Double Mutations of NRAS and KRAS in Acute Myeloid Leukemia and Myelodysplastic Syndrome Are Associated with Monocytic Differentiation, Multilineage Dysplasia, Increased Myeloblasts and Prior Chemotherapy.
Su S Chen, Zhuang Zuo, Rajyalakshmi Luthra, Gary Lu, Gautam Borthakur, Sa A Wang, L Jeffrey Medeiros, C Cameron Yin. University of Texas M.D. Anderson Cancer Center, Houston
Background: Activating mutations of KRAS and NRAS have been frequently reported in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), especially cases with monocytic differentiation, and these mutations predict poorer clinical outcome. Most mutations of RAS are single point mutations occurring in codons 12, 13 or 61. Cases with double RAS mutations are rarely reported. We report the clinicopathologic and molecular genetic features of 24 cases with double RAS mutation.
Design: We searched for cases of AML or MDS that were assessed for both KRAS and NRAS mutations. The clinical and laboratory data were obtained from the medical records. Mutation analysis of KRAS and NRAS was performed using pyrosequencing. Mutation analysis of NPM1 and FLT3 was performed using PCR and capillary electrophoresis. Mutation analysis of CEBPA was performed using Sanger sequencing.
Results: We identified 24 cases that had two RAS gene mutations. 13 cases had mutations in KRAS and NRAS and 11 cases had two NRAS mutations. The overall frequency of double RAS mutations represent approximately 10% of all cases with RAS mutation. This study group included 18 cases of AML, 3 cases of MDS, and 3 cases of chronic myelomonocytic leukemia. The AML case were further classified as: AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n=6), therapy-related AML (n=4), acute monocytic leukemia (n=4), and acute myelomonocytic leukemia (n=4). Morphologically, significant dysplasia was noted in erythrocytes, megakaryocytes and granulocytes in 13 (54%), 19 (79%) and 18 (75%) cases, respectively. 15/24 (63%) of cases showed monocytic differentiation. Cytogenetic analysis showed an aberrant karyotype in 16 cases: inv(16)(p13.1q22) in 4, t(16;16)(p13.1;q22) in 2, complex karyotype in 6, del(20q) in 1, -7 in 1, t(10;12)(q24;p13) in 1, and a marker chromosome in 1. Molecular analyses showed mutations in NPM1, FLT3 and CEBPA in 5/15 (33%), 3/22 (14%) and 1/9 (11%) of cases, respectively. All patients received chemotherapy. With a median follow-up of 13 months (range, 3-86 months), 7 patients were in clinical remission, 7 died of disease, 3 had persistent disease, and 7 were lost to follow-up.
Conclusions: Cases with double RAS mutations are common, representing approximately 10% of all cases with RAS mutation. These cases are often associated with monocytic differentiation, multilineage dysplasia, increased myeloblasts, inv(16)(p13.1q22)/t(16;16)(p13.1;q22) or prior chemotherapy.
Monday, February 28, 2011 1:45 PM
Platform Session: Section B, Monday Afternoon